The knowledge of how the expression of specific genes is regulated in animal cells is basic to our understanding of the orderly processes of normal development and differentiation, as well as the derangements of neoplasia, teratogenesis, and those inherited diseases in which gene expression is aberrant. The broad aims of this project are to investigate the biochemical and genetic mechanisms by which hormones control gene expression in mammalian cells. The hormonal induction of tyrosine aminotransferase (TAT) in rat hepatoma cells (HTC) in tissue culture has been utilized as a model system. I will study various aspects of the posttranscriptional control of TAT synthesis by insulin, dexamethasone, and serum, and the ways in which they interact to regulate the cellular content of a single enzyme. I will also investigate the mechanisms by which these humoral effectors modulate amino acid transport, ribosomal distribution, and protein synthesis and degradation in HTC cells. The genetic regulation of enzyme induction will be explored in hybrid cells in circumstances in which enzyme inducibility can be assessed separately from the expression of the TAT structural genes. Finally, I will attempt to apply some of the above approaches to the problem of insulin resistance manifest in certain inherited neurologic and endocrine diseases, by studying various parameters of insulin responsiveness in cultured skin fibroblasts from patients with these mendelian diseases.